The action of the enzyme renin on renin substrate, a pseudoglobulin in blood plasma, produces a polypeptide angiotensin I, also known as hypertensin I. The latter is converted by an enzyme to angiotensin II, also known as hypertensin II or angiotonin. Angiotensin II is an active pressor substance which is present in the plasma of individuals with hypertension in quantities sufficient to maintain elevated blood pressure. Inhibition of the enzyme responsible for the conversion of angiotensin I to angiotensin II serves to remove a cause of essential hypertension.
U.S. Pat. No. 3,832,337 to Ondetti et al. discloses various peptides and acylated peptides which inhibit enzymatic conversion of angiotensin I into angiotensin II, among such peptides being EQU Pyr-Trp-Pro-Arg-Gln-Ilc-Pro-Pro.
Studies on structure-activity relationships concerning peptides as disclosed in U.S. Pat. No. 3,832,337 indicated that a free terminal carboxyl group is needed to obtain potent inhibitors in vitro and in vivo. For example, see the paper by Cushman et al., "Inhibition of Angiotensin-Converting Enzyme by Analogs of Peptides from Bothrops jararaca Venom", Experienta 29, 1032 (1973), Birkhauser Verlag, Basel, Switzerland. However, it has now been found that not only is the above nonapeptide an inhibitor of angiotensin I induced hypertension, but esters and amides of such nonapeptide are useful for such purpose as well. This is surprising inasmuch as such esters and amides show very low or no detectable enzyme inhibition activity in vitro. Generally, in vitro activity of peptides in this area usually corresponds to in vivo activity thereof. Accordingly, it is indeed unexpected that such esters and amides are potent inhibitors of angiotensin I induced hypertension.